Abstract

Nutritional chemoprevention is a promising approach for prostate cancer (PCa) management. Resveratrol (Res), found in plants, has antioxidant, cardioprotective, anti-inflammatory and anticancer properties. Res may be considered as both a chemopreventive and chemotherapeutic agent on the basis of molecular and preclinical studies. We propose to investigate novel epigenetic mechanisms of the chemopreventive and anticancer effects of Res. We discovered that Res down-regulates metastasis-associated protein 1 (MTA1) by causing its proteasomal degradation. MTA1 levels correlate with cancer aggressiveness and metastases and, as a part of the nucleosome remodeling deacetylation (NuRD) complex, MTA1 plays a role in chromatin remodeling and transcriptional repression.

We hypothesize that MTA1 nuclear overexpression promotes PCa progression and metastasis by enhancing MTA1/HDAC1/NuRD deacetylation activity. We further hypothesize that Res, as a potent inhibitor of MTA1, exerts its anticancer effects, at least in part, through blocking MTA1/HDAC1/NuRD-mediated deacetylation. We propose: (1) determine the effects of Res on MTA1-mediated epigenetic modifications of PTEN and HIF-1α. We will use PCa cells with silenced MTA1 (shRNA-mediated knockdown) to examine the acetylation state of PTEN and HIF-1α in the presence or absence of Res. Transcriptional activation/repression of downstream signaling (PI3K/Akt) or target genes (VEGF) will be used as readouts. (2) evaluate MTA1-associated epigenetic anticancer effects of Res analogues in PCa. We will compare biopotency of natural and synthetic Res analogues in inhibiting MTA1, cell proliferation, invasion and migration in vitro. (3) evaluate MTA1-mediated Res chemopreventive and therapeutic efficacy in PCa mouse models. a. we will use orthotopic PCa xenografts to evaluate MTA1-mediated effects of Res on PCa initiation, progression and metastasis; b. we will evaluate Res chemopreventive and therapeutic effects using autochthonous, prostate-specific Pten −/− mouse model.

Our study is the first to identify MTA1 as a specific molecular target of Res, further defining a novel epigenetic mechanism of Res anticancer activity as an HDAC inhibitor. The mechanism-based studies will significantly contribute to a better understanding of the role of MTA1 as an upstream epigenetic regulator of tumor suppressors and oncogenes. The results from this study will aid the development of preventive and curative strategies based on Res, its potent analogues, and synergy with other “epigenetic” agents. Our preclinical studies will provide a powerful base for initiating clinical trials in men.